The genes encoded by our DNA form the template for the RNA and proteins that make up our cells and tissues and allow them to carry out their normal functions. However, not all of our DNA is expressed simultaneously by every cell. Epigenetic regulation changes the packaging and handling of DNA, providing genetically identical cells the ability to produce dramatically different patterns of gene expression. It allow for cells and tissues to silence the genes they don't need, and activate the genes they do. Now, advances in sequencing technologies are revealing that epigenetic regulators are among the most frequently altered genes in cancer. In many cancers, these epigenetic regulators do not function properly, often as a result of mutations in their DNA sequence. Our group and others have identified Multiple Myeloma SET domain-containing protein (MMSET) as an important epigenetic regulator in cancer. In normal cells, MMSET modifies the packaging of DNA in specific chromosomal regions to activate expression of genes. However, in many cancers, changes in the MMSET gene result in increased production of MMSET, which can cause increased cell growth and is associated with poor patient prognosis. Recently, a hyperactive form of MMSET was detected in several cancers of lymphoid cells, including relapsed pediatric acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL). This hyperactive form is generated by a single mutation at position 1099 in the MMSET gene (MMSET E1099K). However, the biological function of MMSET E1099K in cancers is not fully understood. We hypothesize that the E1099K mutation leads to alterations in DNA packaging and handling, which results in changes in gene expression and in turn drives progression of lymphoid malignancies. We will test this hypothesis by examining the gene expression changes and biological consequences of the MMSET E1099K mutant in ALL and MCL cells and in mice. The mouse mutant will also help us learn how MMSET collaborates with other important drivers of cancer pathology. These studies will further our knowledge of lymphoid malignancy progression, as well as help us learn how to best design cancer therapies to target epigenetic dysregulation generated by MMSET E1099K.